Toxicity profile of the immunomodulatory thalidomide analogue, lenalidomide : Phase I clinical trial of three dosing schedules in patients with solid malignancies

Thalidomide is an anti-angiogenic agent currently used to treat patients with malignant cachexia or multiple myeloma. Lenalidomide (CC-5013) is an immunomodulatory thalidomide analogue licensed in the United States of America (USA) for the treatment of a subtype of myelodysplastic syndrome. This two-centre, open-label phase I study evaluated dose-limiting toxicities in 55 patients with malignant solid tumours refractory to standard chemotherapies. Lenalidomide capsules were consumed once daily for 12 weeks according to one of the following three schedules: (I) 25 mg daily for the first 7 d, the daily dose increased by 25 mg each week up to a maximum daily dose of 150 mg; (II) 25 mg daily for 21 d followed by a 7-d rest period, the 4-week cycle repeated for 3 cycles; (III) 10 mg daily continuously. Twenty-six patients completed the study period. Two patients experienced a grade 3 hypersensitivity rash. Four patients in cohort I and 4 patients in cohort II suffered grade 3 or 4 neutropaenia. In 2 patients with predisposing medical factors, grade 3 cardiac dysrhythmia was recorded. Grade 1 neurotoxicity was detected in 6 patients. One complete and two partial radiological responses were measured by computed tomography scanning; 8 patients had stable disease after 12 weeks of treatment. Fifteen patients remained on treatment as named patients; 1 with metastatic melanoma remains in clinical remission 3.5 years from trial entry. This study indicates the tolerability and potential clinical efficacy of lenalidomide in patients with advanced solid tumours who have previously received multi-modality treatment. Depending on the extent of myelosuppressive pre-treatment, dose schedules (II) or (III) are advocated for large-scale trials of long-term administration. © 2006 Elsevier Ltd. All rights reserved.

Phase II trial of Oxaliplatin and 5-Fluorouracil/Leucovorin combination in epithelial ovarian carcinoma relapsing within 2 years of platinum-based therapy

Objective To evaluate the efficacy and toxicity of Oxaliplatin and 5-Fluorouracil (5-FU)/Leucovorin (LV) combination in ovarian cancer relapsing within 2 years of prior platinum-based chemotherapy in a phase II trial. Methods Eligible patients had at least one prior platinum-based chemotherapy regimen, elevated CA-125 ≥ 60 IU/l, radiological evidence of disease progression and adequate hepatic, renal and bone marrow function. Patients with raised CA-125 levels alone as marker of disease relapse were not eligible. Oxaliplatin (85 mg/m 2) was given on day 1, and 5-Fluorouracil (370 mg/m 2) and Leucovorin (30 mg) was given on days 1 and 8 of a 14-day cycle. Results Twenty-seven patients were enrolled. The median age was 57 years (range 42-74 years). The median platinum-free interval (PFI) was 5 months (range 0-17 months) with only 30% of patients being platinum sensitive (PFI > 6 months). Six patients (22%) had two prior regimens of chemotherapy. A total of 191 cycles were administered (median 7; range 2-12). All patients were evaluable for toxicity. The following grade 3/4 toxicities were noted: anemia 4%; neutropenia 15%; thrombocytopenia 11%; neurotoxicity 8%; lethargy 4%; diarrhea 4%; hypokalemia 11%; hypomagnesemia 11%. Among 27 enrolled patients, 20 patients were evaluable for response by WHO criteria and 25 patients were evaluable by Rustin's CA-125 criteria. The overall response rate (RR) by WHO criteria was 30% (95% CI: 15- 52) [three complete responses (CRs) and three partial responses (PRs)]. The CA-125 response rate was 56% (95% CI: 37-73). Significantly, a 25% (95% CI: 9-53) radiological and a 50% (95% CI: 28-72) CA-125 response rate were noted in platinum resistant patients (PFI < 6 months). The median response duration was 4 months (range 3-12) and the median overall survival was 10 months. Conclusion Oxaliplatin and 5-Fluorouracil/ Leucovorin combination has a good safety profile and is active in platinum-pretreated advanced epithelial ovarian cancer. © 2004 Elsevier Inc. All rights reserved.

Development of empirical equations for irradiance profile of a standard parabolic trough collector using Monte Carlo ray tracing technique

Irradiance profile around the receiver tube (RT) of a parabolic trough collector (PTC) is a key effect of optical performance that affects the overall energy performance of the collector. Thermal performance evaluation of the RT relies on the appropriate determination of the irradiance profile. This article explains a technique in which empirical equations were developed to calculate the local irradiance as a function of angular location of the RT of a standard PTC using a vigorously verified Monte Carlo ray tracing model. A large range of test conditions including daily normal insolation, spectral selective coatings and glass envelop conditions were selected from the published data by Dudley et al. [1] for the job. The R2 values of the equations are excellent that vary in between 0.9857 and 0.9999. Therefore, these equations can be used confidently to produce realistic non-uniform boundary heat flux profile around the RT at normal incidence for conjugate heat transfer analyses of the collector. Required values in the equations are daily normal insolation, and the spectral selective properties of the collector components. Since the equations are polynomial functions, data processing software can be employed to calculate the flux profile very easily and quickly. The ultimate goal of this research is to make the concentrating solar power technology cost competitive with conventional energy technology facilitating its ongoing research.

Coordinated control of grid connected photovoltaic reactive power and battery energy storage systems to improve the voltage profile of a residential distribution feeder

Increasing penetration of photovoltaic (PV) as well as increasing peak load demand has resulted in poor voltage profile for some residential distribution networks. This paper proposes coordinated use of PV and Battery Energy Storage (BES) to address voltage rise and/or dip problems. The reactive capability of PV inverter combined with droop based BES system is evaluated for rural and urban scenarios (having different R/X ratios). Results show that reactive compensation from PV inverters alone is sufficient to maintain acceptable voltage profile in an urban scenario (low resistance feeder), whereas, coordinated PV and BES support is required for the rural scenario (high resistance feeder). Constant as well as variable droop based BES schemes are analyzed. The required BES sizing and associated cost to maintain the acceptable voltage profile under both schemes is presented. Uncertainties in PV generation and load are considered, with probabilistic estimation of PV generation and randomness in load modeled to characterize the effective utilization of BES. Actual PV generation data and distribution system network data is used to verify the efficacy of the proposed method.

Meta-analysis of individual patient data from randomized trials of chemotherapy plus cetuximab as first-line treatment for advanced non-small cell lung cancer

OBJECTIVES: Four randomized phase II/III trials investigated the addition of cetuximab to platinum-based, first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). A meta-analysis was performed to examine the benefit/risk ratio for the addition of cetuximab to chemotherapy. MATERIALS AND METHODS: The meta-analysis included individual patient efficacy data from 2018 patients and individual patient safety data from 1970 patients comprising respectively the combined intention-to-treat and safety populations of the four trials. The effect of adding cetuximab to chemotherapy was measured by hazard ratios (HRs) obtained using a Cox proportional hazards model and odds ratios calculated by logistic regression. Survival rates at 1 year were calculated. All applied models were stratified by trial. Tests on heterogeneity of treatment effects across the trials and sensitivity analyses were performed for all endpoints. RESULTS: The meta-analysis demonstrated that the addition of cetuximab to chemotherapy significantly improved overall survival (HR 0.88, p=0.009, median 10.3 vs 9.4 months), progression-free survival (HR 0.90, p=0.045, median 4.7 vs 4.5 months) and response (odds ratio 1.46, p<0.001, overall response rate 32.2% vs 24.4%) compared with chemotherapy alone. The safety profile of chemotherapy plus cetuximab in the meta-analysis population was confirmed as manageable. Neither trials nor patient subgroups defined by key baseline characteristics showed significant heterogeneity for any endpoint. CONCLUSION: The addition of cetuximab to platinum-based, first-line chemotherapy for advanced NSCLC significantly improved outcome for all efficacy endpoints with an acceptable safety profile, indicating a favorable benefit/risk ratio.

A profile of Australian travel journalists' professional views and ethical standards

Despite significant changes in mainstream journalism in recent decades, journalistic fields beyond the news have been little explored. In an attempt to contribute to a deeper understanding of such fields, this article examines the role perceptions of 85 Australian travel journalists. By viewing travel journalism as a distinct field of practice that is affected by a unique mix of influences, this study identifies five dimensions of practitioners’ role perceptions. These relate to travel journalists’ views of themselves as Cultural Mediators, Critics, Entertainers, Information Providers and Travellers. In addition, the study examines in some depth the ethical standards of travel journalists. Determinants of these views and standards are explored. The study argues that, in light of travel journalists’ increasingly important role in reporting about foreign places, more remains to be done to promote travel stories that show a deeper understanding of other cultures and which contain a more critical appraisal of destinations.

Profile of women detected drink driving via Roadside Breath Testing (RBT) in Queensland, Australia, between 2000 and 2011

Background Drink driving among women is a growing problem in many motorised countries. While research has shown that male and female drink drivers differ on a number of characteristics, few studies have addressed the circumstances surrounding women’s drink driving offences specifically. Aim To add to previous research by comparing apprehension characteristics among men and women and to extend the understanding of the female drink driving problem by investigating the drink driving characteristics that are unique to women. Results The sample consisted of the 248,173 (21.5% women) drink drivers apprehended between 2000 and 2011 in Queensland, Australia. Gender comparisons showed that women were older, had lower levels of reoffending, and were more likely to be apprehended in Major Cities compared to men. Comparisons of age group and reoffending and non-reoffending among female drink drivers only revealed that higher BAC readings were more common among younger women. Moreover, a substantial minority (13.7%) of women aged 24 years or younger were apprehended with a BAC below0.05%, reflecting a breach of the zero tolerance BAC for provisional licence holders in Australia. Older women were more likely to be charged with a ‘failure to provide a test’ offence as a result of refusing to provide a breath or blood sample, indicating that drink driving is associated high levels of stigma for this group. Reoffending occurred among 16.2% of the female drink drivers and these drivers were more likely than non-reoffending drivers to record a mid to high range BAC, to be aged 30-39 or below 21years, and to be apprehended in Inner Regional or Remote locations. Conclusion Findings highlight the unique circumstances and divergent needs of female drink drivers compared to male drivers and for different groups of female drivers.

Food reward sensitivity predicts overconsumption of high-fat snack food

Overconsumption of snack foods has been linked to rising rates of obesity, with our ‘obesogenic’ environment and its abundance of palatable, high-calorie foods and associated cues especially implicated. However, it is clear that some individuals are particularly susceptible to overconsumption and weight gain. It was hypothesised that individuals sensitive to the rewarding properties of palatable foods, and associated stimuli, would show elevated consumption. Snack food intake was measured in 50 adults (mean age 34.5 years, BMI 23.9 kg/m2, 56% female) in a repeated measures design, both with and without a ‘food cue’. Trait (BIS/BAS scales), behavioural (computerised CARROT) and food reward were assessed. Sensitivity to food reward, but not generalised reward, was positively associated with snack food intake. This relationship was not affected by the presence of a food cue. Findings are discussed in the context of implications for weight management.

Load profile based determination of distribution feeder configuration by dynamic programming

This paper presents a new method to determine feeder reconfiguration scheme considering variable load profile. The objective function consists of system losses, reliability costs and also switching costs. In order to achieve an optimal solution the proposed method compares these costs dynamically and determines when and how it is reasonable to have a switching operation. The proposed method divides a year into several equal time periods, then using particle swarm optimization (PSO), optimal candidate configurations for each period are obtained. System losses and customer interruption cost of each configuration during each period is also calculated. Then, considering switching cost from a configuration to another one, dynamic programming algorithm (DPA) is used to determine the annual reconfiguration scheme. Several test systems were used to validate the proposed method. The obtained results denote that to have an optimum solution it is necessary to compare operation costs dynamically.

Effectiveness of reactive power capability of photo voltaic inverters to maintain voltage profile in a residential distribution feeder

Large penetration of rooftop PVs has resulted in unacceptable voltage profile in many residential distribution feeders. Limiting real power injection from PVs to alleviate over voltage problem is not feasible due to loss of green power and hence corresponding revenue loss. Reactive capability of the PV inverter can be a solution to address over voltage and voltage dip problems to some extent. This paper proposes an algorithm to utilize reactive capability of PV inverters and investigate their effectiveness for voltage improvement based on R/X ratio of the feeder. The length and loading level of the feeder for a particular R/X ratio to have acceptable voltage profile is also investigated. This can be useful for suburban design and residential distribution planning. Furthermore, coordination among different PVs using residential smart meters via a substation based controller is also proposed.

Effectiveness of reactive power capability of photo voltaic inverters to maintain acceptable voltage profile in a residential distribution system

Integration of rooftop PVs and increasing peak demand in the residential distribution networks has resulted in unacceptable voltage profile. Curtailing PV generation to alleviate overvoltage problem and making regular network investment to cater peak demand is not always feasible. Reactive capability of the PV inverter can be a solution to address voltage dip and over voltage problems to some extent. This paper proposes an algorithm to utilize reactive capability of PV inverters and investigate their effectiveness on feeder length and R/X ratio of the line. Feeder loading level for a particular R/X ratio to have acceptable voltage profile is also investigated. Furthermore, the need of appropriate feeder distances and R/X ratio for acceptable voltage profile, which can be useful for suburban design and distribution planning, is explored.

TNF and TNF receptor expression and insulin sensitivity in human omental and subcutaneous adipose tissue--influence of BMI and adipose distribution

Tumour necrosis factor (TNF)alpha is implicated in the relationship between obesity and insulin resistance/ type 2 diabetes. In an effort to understand this association better we (i) profiled gene expression patterns of TNF, TNFR1 and TNFR2 and (ii) investigated the effects of TNF on glucose uptake in isolated adipocytes and adipose tissue explants from omental and subcutaneous depots from lean, overweight and obese individuals. TNF expression correlated with expression of TNFR2, but not TNFR1, and TNF and TNFR2 expression increased in obesity. TNFR1 expression was higher in omental than in subcutaneous adipocytes. Expression levels of TNF or either receptor did not differ between adipocytes from individuals with central and peripheral obesity. TNF only suppressed glucose uptake in insulin-stimulated subcutaneous tissue and this suppression was only observed in tissue from lean subjects. These data support a relationship between the TNF system and body mass index (BMI), but not fat distribution, and suggest depot specificity of the TNF effect on glucose uptake. Furthermore, adipose tissue from obese subjects already appears insulin 'resistant' and this may be a result of the increased TNF levels.

Optimal sizing of combined PV-energy storage for a grid-connected residential building

In this paper, load profile and operational goal are used to find optimal sizing of combined PV-energy storage for a future grid-connected residential building. As part of this approach, five operational goals are introduced and the annual cost for each operation goal has been assessed. Finally, the optimal sizing for combined PV-energy storage has been determined, using direct search method. In addition, sensitivity of the annual cost to different parameters has been analyzed.

Direct lipid profiling of single cells from inkjet printed microarrays

The on-demand printing of living cells using inkjet technologies has recently been demonstrated and allows for the controlled deposition of cells in microarrays. Here, we show that such arrays can be interrogated directly by robot-controlled liquid microextraction coupled with chip-based nanoelectospray mass spectrometry. Such automated analyses generate a profile of abundant membrane lipids that are characteristic of cell type. Significantly, the spatial control in both deposition and extraction steps combined with the sensitivity of the mass spectrometric detection allows for robust molecular profiling of individual cells. © 2012 American Chemical Society.

A simple model for the establishment of tick-borne pathogens of Ixodes scapularis : a global sensitivity analysis of R0

The basic reproduction number of a pathogen, R 0, determines whether a pathogen will spread (R0>1R 0>1), when introduced into a fully susceptible population or fade out (R0<1R 0<1), because infected hosts do not, on average, replace themselves. In this paper we develop a simple mechanistic model for the basic reproduction number for a group of tick-borne pathogens that wholly, or almost wholly, depend on horizontal transmission to and from vertebrate hosts. This group includes the causative agent of Lyme disease, Borrelia burgdorferi, and the causative agent of human babesiosis, Babesia microti, for which transmission between co-feeding ticks and vertical transmission from adult female ticks are both negligible. The model has only 19 parameters, all of which have a clear biological interpretation and can be estimated from laboratory or field data. The model takes into account the transmission efficiency from the vertebrate host as a function of the days since infection, in part because of the potential for this dynamic to interact with tick phenology, which is also included in the model. This sets the model apart from previous, similar models for R0 for tick-borne pathogens. We then define parameter ranges for the 19 parameters using estimates from the literature, as well as laboratory and field data, and perform a global sensitivity analysis of the model. This enables us to rank the importance of the parameters in terms of their contribution to the observed variation in R0. We conclude that the transmission efficiency from the vertebrate host to Ixodes scapularis ticks, the survival rate of Ixodes scapularis from fed larva to feeding nymph, and the fraction of nymphs finding a competent host, are the most influential factors for R0. This contrasts with other vector borne pathogens where it is usually the abundance of the vector or host, or the vector-to-host ratio, that determine conditions for emergence. These results are a step towards a better understanding of the geographical expansion of currently emerging horizontally transmitted tick-borne pathogens such as Babesia microti, as well as providing a firmer scientific basis for targeted use of acaricide or the application of wildlife vaccines that are currently in development.